The Feats of a Frontiersman in Cancer Research

by: Brittany Raffa
Date: February 2008

Dr. Judah Folkman, surgeon and researcher who pioneered the way to fight cancer by starving tumors of their blood supply, died at age 74 on January 14, 2008. Folkman was changing planes at a Denver airport while making his way to Vancouver, Canada for a conference when he succumbed to a heart attack, said family members. Where else would a man who has changed the course of modern medicine be going at his death if not to a scientific meeting?

Folkman is a frontiersman in cancer research because of his discovery that tumors can stimulate the growth of new blood vessels to supply themselves with the necessary nutrients and oxygen. Folkman was considered an outcast by fellow scientists for more than 25 years before he could provide substantial evidence of his hypothesis in the mid-1990s. During all this time he never let this criticism and doubt halt his research.

It was in the 1960s while serving as a lieutenant at the National Naval Medical Center in Bethesda, MD that he first stumbled across evidence supporting the idea. Folkman and his colleague Frederick Becker removed a thyroid gland from a rabbit and injected it with cancer cells while keeping it alive in a glass dish. It became apparent that the tumor created by the injected cancer cells grew until it reached about a million cells, the size of a pinhead. Yet, when the gland was implanted into a rabbit, the tumor resumed growing until it finally killed the rabbit. Folkman believed that nutrients were unable to diffuse through the tumor to reach the innermost cells once the tumor had grown to a particular size, which in the case of the rabbit's gland was about the size of a pinhead. This caused the growth of the tumor to halt. However, when the tumor was placed in the animal's body, new blood vessels were created from original vessels which grew into the tumor mass and provided the cells inside with the nutrients needed to grow.

Folkman later worked at Harvard where he persisted in studying the phenomena with experiments on tumors in rabbit eyes. He implanted small tumors in two areas of the rabbit eye: near the iris which is rich in blood vessels and near the cornea, where there are no vessels. The tumor in the iris grew and new blood vessels were observed forming nearby. In contrast, the tumor in the cornea did not grow. Folkman described these results and argued that stopping angiogenesis, the formation and growth of new blood vessels, would stop tumor growth in the New England Journal of Medicine in 1971. Immediately afterward, critics tried to prove him wrong. They almost succeeded when a group of researchers observed the development of new blood vessels in the iris after implanting uric acid crystals. Two years later the actual reason for the growth was identified to be white blood cells that secreted a chemical in the presence of the uric acid crystals, causing new blood vessels to form.

In the 1970s the Folkman lab applied for the first time for a grant to obtain funds for further research on angiogenesis. The National Cancer Institute's response was blunt:

It is common knowledge that the hypervascularity associated with tumors is due to dilation of host vessels and not new vessels and that this dilation is probably caused by the side effects of dying tumor cells. Therefore, tumor growth cannot be dependent upon blood vessel growth any more than infection is dependent upon pus.

In 1985, a chance event caused a major breakthrough in the Folkman lab. Spores of a fungus randomly landed on a laboratory dish where blood vessels were being grown and consequently stopped their growth. By experimenting more with the fungus, researchers discovered an astounding substance produced by the fungus: the first angiogenesis inhibitor, a molecule capable of stopping the growth of vessels and thereby stopping the growth of tumors. The next groundbreaking event followed in the mid-1990s when Folkman and Michael O'Reilly isolated two other inhibitors, known as angiostatin and endostatin. The effect of these inhibitors was significant because they blocked tumor growth in the mice.

The discoveries of Folkman remained out of the spotlight until 1998, when Nobel Prize winner James Watson, co-founder of the DNA helix structure model, mentioned in a dinner with a New York Times reporter that "Judah Folkman is going to cure cancer in two years." Suddenly Folkman was engulfed with interview requests and e-mails and phone calls from cancer patients wanting information about the drug, which had not even been tested on humans. Folkman tried to bring people to reality about the progress of the research by saying, "If you have cancer and you are a mouse, we can take good care of you."

Folkman explained how he felt during this period in a 2002 interview with Scientific American: "At the beginning I felt enormous pressure.[The news] raised expectations and demand for angiogenesis inhibitors before these drugs had completed testing in clinical trials..For any type of therapy there is always a dilemma about when to inform the public. If it's too early, then physicians are besieged by calls from patients for drugs that cannot be obtained. If too late, then critics say that hope was destroyed for patients with advanced disease."

Angiogenesis drugs have now been tested in human clinical trials with ranging results. In one trial, in which patients with cancer affecting nerve cells that produce hormones were given endostatin, only four out of 42 patients had experienced long-term positive effects. More recent antiangiogenic therapies have been successful: In 2004, the FDA approved Avastin for patients with colorectal cancer who are undergoing chemotherapy at the same time; up to now it has also been approved for certain cases of lung, breast and kidney cancer. Other angiogenesis inhibitors have been approved to fight macular degeneration, a progressive vision-impairing disease that destroys the central area of the retina. There are currently at least 40 compound affecting angiogenesis that are tested in humans to battle several cancer types, heart disease, eye diseases and diabetes-related disorders.

The scientist who was known to work 21 hours a day and whose true name is Moses Judah Folkman, was born February 24, 1933 in Cleveland. His father was a rabbi and Judah and his brother and sister went regularly with him to visits sick congregants. Folkman was passionate about science from early on. His grandfather wanted to buy him a Jeep for his bar mitzvah present, but Folkman convinced him to rather buy a top-notch microscope. As part of a high-school science project, Folkman kept a rat's heart beating outside its body for 30 minutes by a device composed of a toy refrigerator and a bicycle pump. Despite his father's urging to become a rabbi, Folkman insisted that he could bring about more good as a medic. His father responded with the request that he should therefore become a "rabbi-like doctor," which he fulfilled.

Folkman graduated with honors as a pre-med student at Ohio State University where he studied new ways to treat liver cancer and co-published several papers. By the end of his freshman year at Ohio State he was performing surgeries on dogs under the supervision of Dr. Robert Zollinger, then the president of the American College of Surgeons. He also designed a device that cooled the liver during surgery. At the age of 20 he enrolled in Harvard Medical School. During his time at Harvard, Folkman and MIT student Fred Vanderschmidt developed one of the first implantable pacemakers. After graduation in 1957, he worked at the naval center in Bethesda and later became the chief surgeon at the Children's Hospital Boston from 1967 to 1981. In 1981, he stepped down from his position as chief surgeon and became director of the hospital's Vascular Biology Program.

Rakesh Jain, professor of tumor biology at Harvard Medical School and colleague of Folkman, recalled inviting Folkman to present a lecture to his class at the Massachusetts Institute of Technology in 1983: "He was one of the most mesmerizing speakers I have known in my life," said Jain, "He humanizes science.that's a quality I try to emulate."

"The problem of understanding the phenomenon of angiogenesis, of working out its biology, of connecting it to a large family of clinical diseases once thought to be totally separate entities, seems to have been tackled in somewhat the same way that the author E.L. Doctorow describes what it is like to write a novel. 'Writing is like driving at night,' he said, 'You cannot see beyond the headlights, but you can make the whole trip that way.'" Judah Folkman, M.D. (Perspectives, February 1994).

JYI has a peer-review process through which undergraduate research editors work with faculty mentors at their institutions to determine the validity of journal submissions. This process closely mimics those found in other professional research journals.